PROJECT SUMMARY Sleep is a fundamental behavior that is widely observed across the animal kingdom. Sleep is characterized by repeated brain state transitions between rapid eye movement (REM) and non-REM (NREM) sleep. Sleep states and transitions between them are regulated by reciprocal interactions between neuronal populations and homeostatic need. At present, we lack detailed understanding of the brain mechanisms controlling sleep. The preoptic area of the hypothalamus is crucial for sleep control and contains neurons that are active during sleep and are necessary for sleep. One challenge is that wake, REM and NREM-active neurons are intermingled within the preoptic area, making it difficult to specifically target REM and NREM-active neurons for circuit analysis. We previously showed that subsets of preoptic neurons expressing cholecystokinin or corticotropin- releasing hormone promote both REM and NREM sleep whereas tachykinin 1 expressing neurons promote only NREM sleep. These findings serve as a valuable entry point for exploring the role of the preoptic sleep circuitry in controlling REM and NREM sleep, brain state transitions and homeostatic regulation of both sleep states. In Aim 1, we will investigate circuit mechanisms to understand how these subsets of preoptic neurons regulate REM and NREM sleep through their interactions with downstream targets. In Aim 2, we will investigate the mechanisms how preoptic sleep neurons integrate homeostatic pressure in response to REM and NREM sleep loss. Accomplishing these aims will provide important circuit-level insights into the neural basis of sleep regulation, with potential relevance to understand and develop novel therapeutic interventions for sleep disorders.